rs1555598687
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000152.5(GAA):c.241C>T(p.Gln81Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000152.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.241C>T | p.Gln81Ter | stop_gained | 2/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.241C>T | p.Gln81Ter | stop_gained | 2/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460238Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726448
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 20, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2019 | This sequence change creates a premature translational stop signal (p.Gln81*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual glycogen storage disease type II (PMID: 25526786). ClinVar contains an entry for this variant (Variation ID: 557360). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Jun 15, 2020 | This variant, c.281C>T (p.Gln81Ter), is a nonsense variant which is predicted to cause nonsense mediated decay and lack of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. Three siblings, all with low residual GAA activity meeting PP4, were reported to be compound heterozygous for the variant and a pathogenic missense change, c.2238G>C (p.Trp746Cys) (PMID 25526786). However, the intrans data was used in the assessment of p.Trp746Cys and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 557360, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PP4. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at